This application addresses Broad Challenge Area (5), Comparative Effectiveness Research, and specifically Comparative Effectiveness Research on Cancer Screening, 05-CA-102. Significance: With our health care system in financial crisis, and colorectal cancer (CRC) both the second leading cause of cancer death and a largely preventable disease, there is a critical need for high quality comparative effectiveness studies of CRC screening modalities. The recent United States Preventive Services Task Force (USPTF) decision analysis found no difference in life-years gained by CRC screening using colonoscopy every 10 years vs. annual fecal immunochemical testing in individuals aged 50 to 75.1 However, although studies comparing FIT and colonoscopy have been conducted in non-screening populations2, 3 and populations outside the United States4-6, no studies using average-risk patients have been conducted in the United States directly comparing these methods. We will compare the test characteristics of a fecal immunochemical test (FIT) with colonoscopy in 700 average risk individuals undergoing screening colonoscopy;assess patient preferences for FIT vs. colonoscopy in the study sample;and compare projected costs using these screening strategies. This study will help lay the foundation for a multi-site primary care practice- based trial for two-step CRC screening (FIT followed by colonoscopy for those who test positive on FIT) using our Iowa Research Network (IRENE). IRENE is a primary care, practice-based research network of over 300 family physicians in 200 practices. The results of this pilot and the future larger scale study would allow specific clinical recommendations to be developed and recommended based on actual normal risk US data rather than on high risk, non-screening US populations and/or non-US data alone, as has been the case until now. This study will provide critical information on the test characteristics of a fecal immunochemical test for colon cancer screening in an average risk U.S. population and individual's attitudes and preferences for these tests, which will help lay the foundation for a larger colorectal cancer screening trial to be conducted in our primary care practice-based rural research network, the Iowa Research Network. The larger, future trial will involve fecal immunochemical testing, followed by colonoscopy for those who are FIT positive, in a sample of average-risk individuals across the state of Iowa.